EP0001924B2 - Pharmaceutical composition for administering choline - Google Patents

Pharmaceutical composition for administering choline Download PDF

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Publication number
EP0001924B2
EP0001924B2 EP19780300587 EP78300587A EP0001924B2 EP 0001924 B2 EP0001924 B2 EP 0001924B2 EP 19780300587 EP19780300587 EP 19780300587 EP 78300587 A EP78300587 A EP 78300587A EP 0001924 B2 EP0001924 B2 EP 0001924B2
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EP
European Patent Office
Prior art keywords
drug
lecithin
choline
analog
medicament
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
EP19780300587
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German (de)
French (fr)
Other versions
EP0001924A1 (en
EP0001924B1 (en
Inventor
John H. Growdon
Richard J. Wurtman
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Massachusetts Institute of Technology
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Massachusetts Institute of Technology
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Application filed by Massachusetts Institute of Technology filed Critical Massachusetts Institute of Technology
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Publication of EP0001924B1 publication Critical patent/EP0001924B1/en
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole

Definitions

  • This invention relates to the use of lecithin or lecithin analogs for the manufacture of medicaments.
  • These compositions are provided for the administration of a drug with lecithin or lecithin analogs which dissociate to form choline in order to increase acethylcholine levels in brain and other tissues and alleviate human disorders arising as side-effects of the antipsychotic drug as it is specified below in move detail.
  • diseases which affect acetylcholine-containing neurons in the brain or other tissues, and which are treated by drugs that cause undesired side effects by diminishing acetylcholine release; there also exist diseases now treated by other drugs in which the potency and/or efficiency of the drugs could be improved by combining them with choline or natural or synthetic compounds that dissociate to form choline in order thereby to enhance the release of acetylcholine.
  • diseases include both those primarily involving the brain (e.g. diseases of higher cortical functions; psychiatric illnesses; movement disorders) and those involving the peripheral nervous system (e.g. neuromuscular disorders).
  • Tardive dyskinesia is a particularly common movement disorder associated with inadequate release of brain acetylcholine as a result of drug administration for the initial brain disease (e.g. psychosis).
  • Tardive dyskinesia is a choreic movement disorder characterized by involuntary twitches in the tongue, lips, jaw and extremities. It typically occurs in susceptible persons after chronic injestion of neuroleptic drugs and may involve an imbalance in the postulated reciprocal relation between dopaminergic and cholinergic neurons in the basal ganglions.
  • drugs that either block catecholamine synthesis e.g. alpha-methyl-p-tyrosine
  • deplete the brain of monoamines e.g.
  • reserpine, tetrabenazine) or antagonize dopamine's actions on synaptic receptors e.g. pherothiazines, haloperidol
  • synaptic receptors e.g. pherothiazines, haloperidol
  • drugs that indirectly stimulate dopamine receptors e.g. amphetamine, levodopa
  • Drugs assumed to increase the amount of acetylcholine within brain synapses e.g. physostigmine, deanol
  • anticholinergics e.g. scopolamine
  • choline administered by injection or by dietary supplementation increases blood choline levels in the rat; (Cohen et al LIFE SCI., Vol. 16, 1095-1102, 1975 and SCIENCE Vol. 191, 561-562, 1976), this, in turn, increases choline levels in cholinergic neurons within the brain and elsewhere in the body, thereby accelerating the synthesis of acetylcholine, increasing tissue acetylcholine levels, and increasing the amounts of acetylcholine released into brain synapses.
  • This invention is based upon the discovery that lecithin or a physiologically-acceptable lecithin analog that dissociates to form choline, when administered concomitantly with a drug, can, by increasing neuronal acetylcholine levels,
  • lecithin (or a lecithin analog), which dissociates to form choline, is orally administered to a patient together with a drug in order to increase blood levels of choline, and thereby to increase the level of acetylcholine in the brain.
  • the acetylcholine is synthesized from choline and acetyl CoA in a reaction catalyzed by choline acetyl-transferase (CAT). It has been found that the administration of lecithin to form choline potentiates the drug by reducing the incidence or suppressing side effects of the primary drug and/or that lower dosages of the primary drug are needed to attain the desired effects of the drug. While the results obtained will vary from patient to patient, the reduced side effects and increased efficacy observed are sufficiently significant as to justify the conclusion that their reduction is caused by administration of the compound that dissociates to form choline.
  • a choline-producing compound with the lithium salts would allow more effective treatment of the mania, and a reduction in the lithium dose needed by most patients.
  • Another example is myasthenia gravis, a peripheral disease involving the cholinergic nerves that innervate skeletal muscle.
  • the current mode of treatment involves giving drugs like neostigmine (Prostigmin) that increase acetylcholine levels in neuromuscular synapses by blocking the degradation of this neurotransmitter.
  • Prostigmin neostigmine
  • drugs utilized in the present invention are those which cause significant undesirable effects.
  • neuroleptics such as chlorpromazine (THORAZINE®) and haloperidol (HALDOL®) that are used in the treatment of such diseases as schizophrenia, Huntington's disease and Tourette's syndrome.
  • Other drugs that cause undesired effects include phychomotor stimulants such as amphetamine (DEXADRINE®) and methyl-phenidate (RITALINE®) that are used to reat patients with minimal brain dysfunction, hyperactivity and specific dyslexias.
  • drugs utilized in this invention are potentiated.
  • Representative of such drugs are: 1) isoxsuprine (VASODILAN®) and dihydroergotamines (HYDERGINE®) that are used in the treatment of senility; 2) glucocorticosteroids such as triamcinotone (ARISTOCORT®) and prednisone (METICORTEN®) and anticholinesterase drugs such as neostigmine (PROSTIGMIN®) and pyridostigmine (MESTINON®) that are used to treat neuromuscular diseases, including polynigositis and myasthenia gravis; 3) lithium (ESKALITH®) that is used to treat manic-depressive illness and 4) tranquillizers such as phenobarbital (LUMINAL®) and diazepam (VALIUM®) that are used to treat anxiety psychoneurosis.
  • VASODILAN® isoxsuprine
  • HYDERGINE® dihydroergotamines
  • Lecithin or lecithin analogs such as lyso-lecithin are used as the choline source since they are not degraded in the gut, in contrast to choline. They are administered so that a choline level of 20-30 nanomoles/ml and usually between at least 10 and 50 n moles/ml is attained in the patient's blood stream.
  • lecithin in a liquid carrier such as a sweetened elixir
  • lecithin is administered in amounts of between 0.1 and 50 g/day.
  • lecithin is administered in granular form as a tablet or in a capsule, it is employed in amounts of between 0.1 and 100 g/day, usually between 30 and 50 g/day.
  • lecithin is not available as a pure compound and is available in admixture with other phospholipids wherein the lecithin comprises 20-30 weight percent of the mixture.
  • the compound that dissociates to choline is administered concomitantly with the drug.
  • the effect may be achieved when the compound is administered prior to the drug, but the period of time between the compound administration and the drug administration must be less than when acetylcholine concentration reduction begins to occur in the brain.
  • the period of time between administrations is less than 36 hours, preferably less than 24 hours.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Description

    Pharmaceutical composition for administering choline
  • This invention relates to the use of lecithin or lecithin analogs for the manufacture of medicaments. These compositions are provided for the administration of a drug with lecithin or lecithin analogs which dissociate to form choline in order to increase acethylcholine levels in brain and other tissues and alleviate human disorders arising as side-effects of the antipsychotic drug as it is specified below in move detail.
  • There are a number of diseases which affect acetylcholine-containing neurons in the brain or other tissues, and which are treated by drugs that cause undesired side effects by diminishing acetylcholine release; there also exist diseases now treated by other drugs in which the potency and/or efficiency of the drugs could be improved by combining them with choline or natural or synthetic compounds that dissociate to form choline in order thereby to enhance the release of acetylcholine. Such diseases include both those primarily involving the brain (e.g. diseases of higher cortical functions; psychiatric illnesses; movement disorders) and those involving the peripheral nervous system (e.g. neuromuscular disorders). Tardive dyskinesia is a particularly common movement disorder associated with inadequate release of brain acetylcholine as a result of drug administration for the initial brain disease (e.g. psychosis). Tardive dyskinesia is a choreic movement disorder characterized by involuntary twitches in the tongue, lips, jaw and extremities. It typically occurs in susceptible persons after chronic injestion of neuroleptic drugs and may involve an imbalance in the postulated reciprocal relation between dopaminergic and cholinergic neurons in the basal ganglions. Thus, drugs that either block catecholamine synthesis (e.g. alpha-methyl-p-tyrosine), deplete the brain of monoamines (e.g. reserpine, tetrabenazine) or antagonize dopamine's actions on synaptic receptors (e.g. pherothiazines, haloperidol) often suppress tardive dyskinesia, whereas drugs that indirectly stimulate dopamine receptors (e.g. amphetamine, levodopa) often exacerbate the abnormal movements. Drugs assumed to increase the amount of acetylcholine within brain synapses (e.g. physostigmine, deanol), also tend to suppress the chorea of tardive dyskinesia, whereas anticholinergics (e.g. scopolamine), make it worse.
  • It has been shown that choline administered by injection or by dietary supplementation increases blood choline levels in the rat; (Cohen et al LIFE SCI., Vol. 16, 1095-1102, 1975 and SCIENCE Vol. 191, 561-562, 1976), this, in turn, increases choline levels in cholinergic neurons within the brain and elsewhere in the body, thereby accelerating the synthesis of acetylcholine, increasing tissue acetylcholine levels, and increasing the amounts of acetylcholine released into brain synapses. In human beings, oral doses of choline were found to cause dose-related increases in blood choline levels of sufficient magnitude (based on the studies on rats) to enhance brain acetylcholine synthesis and release; choline levels in the cerebrospinal fluid also rose in parallel (Growdon et al., J. Neurochem Vol. 28, 229-231, 1977). It has also been reported (Davis et al. LIFE SCIENCES, Vol. 19, 1507-1516, 1976) in four human patients that the administration of choline decreased the choreiform movements of tardive dyskinesia; no data were provided as to whether or not the drug given concurrently for psychosis (haloperidol, 3 mg per day) continued to be effective during the brief period of choline administration, and it was concluded that the apparent effectiveness of choline had to be interpreted with caution, since "... all four patients with tardive dyskinesia could have been gradually improving during the study" since this disease is characterized by extreme variability of clinical course. Thus, prior to our invention, it had not been known that the concomitant administration of lecithin along with an anti-psychotic drug that causes tardive dyskinesia as a side effect could significantly reduce or prevent the onset of tardive dyskinesia, without blocking the effectiveness of the drug in treating psychosis.
  • This invention is based upon the discovery that lecithin or a physiologically-acceptable lecithin analog that dissociates to form choline, when administered concomitantly with a drug, can, by increasing neuronal acetylcholine levels,
    • 1) reduce or prevent undesirable side effects of the drug associated with inadequate acetylcholine release, and/or
    • 2) potentiate the effectiveness of the drug. The lecithin and the drug may be administered orally such as in tablet, capsule or liquid form or parenterally by intravenous, intramuscular or subcutaneous injection. This invention is useful even with patients having a prior history of the undesirable side effect or of suboptimal therapeutic response or of therapeutic responses requiring a very large drug dose, but who continue taking the drug.
  • In accordance with this invention, lecithin (or a lecithin analog), which dissociates to form choline, is orally administered to a patient together with a drug in order to increase blood levels of choline, and thereby to increase the level of acetylcholine in the brain. The acetylcholine is synthesized from choline and acetyl CoA in a reaction catalyzed by choline acetyl-transferase (CAT). It has been found that the administration of lecithin to form choline potentiates the drug by reducing the incidence or suppressing side effects of the primary drug and/or that lower dosages of the primary drug are needed to attain the desired effects of the drug. While the results obtained will vary from patient to patient, the reduced side effects and increased efficacy observed are sufficiently significant as to justify the conclusion that their reduction is caused by administration of the compound that dissociates to form choline.
  • There are a number of brain and peripheral diseases involving cholinergic neurons that are presently treated with drugs that are only sometimes effective, or that require very large doses of the drugs (with correspondingly greater cost and incidence of side effects); some of these diseases can be more effectively treated by combining the existing drug therapy with concomitant lecithin or a lecithin analog that disscociates to form choline. One example is the mania phases of manic-depressive psychosis, which is currently treated with lithium salts. These salts, as a biochemical side effect, interfered with the uptake of choline into the brain; this tends to reduce brain acetylcholine levels, which exacerbates the mania. The co-administration of a choline-producing compound with the lithium salts would allow more effective treatment of the mania, and a reduction in the lithium dose needed by most patients. Another example is myasthenia gravis, a peripheral disease involving the cholinergic nerves that innervate skeletal muscle. The current mode of treatment involves giving drugs like neostigmine (Prostigmin) that increase acetylcholine levels in neuromuscular synapses by blocking the degradation of this neurotransmitter. Were the compound that dissociates to form choline to be given concomitantly with the cholinesterase-inhibitor, the resulting increases in acetylcholine levels would both potentiate the effect of the cholinesterase-inhibitor and allow for a reduction in its dose.
  • Some of the drugs utilized in the present invention are those which cause significant undesirable effects. Representative of such drugs are neuroleptics, such as chlorpromazine (THORAZINE®) and haloperidol (HALDOL®) that are used in the treatment of such diseases as schizophrenia, Huntington's disease and Tourette's syndrome. Other drugs that cause undesired effects include phychomotor stimulants such as amphetamine (DEXADRINE®) and methyl-phenidate (RITALINE®) that are used to reat patients with minimal brain dysfunction, hyperactivity and specific dyslexias.
  • The effects of some other drugs utilized in this invention are potentiated. Representative of such drugs are: 1) isoxsuprine (VASODILAN®) and dihydroergotamines (HYDERGINE®) that are used in the treatment of senility; 2) glucocorticosteroids such as triamcinotone (ARISTOCORT®) and prednisone (METICORTEN®) and anticholinesterase drugs such as neostigmine (PROSTIGMIN®) and pyridostigmine (MESTINON®) that are used to treat neuromuscular diseases, including polynigositis and myasthenia gravis; 3) lithium (ESKALITH®) that is used to treat manic-depressive illness and 4) tranquillizers such as phenobarbital (LUMINAL®) and diazepam (VALIUM®) that are used to treat anxiety psychoneurosis.
  • Lecithin or lecithin analogs such as lyso-lecithin are used as the choline source since they are not degraded in the gut, in contrast to choline. They are administered so that a choline level of 20-30 nanomoles/ml and usually between at least 10 and 50 n moles/ml is attained in the patient's blood stream. When utilizing lecithin in a liquid carrier, such as a sweetened elixir, it is administered in amounts of between 0.1 and 50 g/day. When lecithin is administered in granular form as a tablet or in a capsule, it is employed in amounts of between 0.1 and 100 g/day, usually between 30 and 50 g/day. Normally, lecithin is not available as a pure compound and is available in admixture with other phospholipids wherein the lecithin comprises 20-30 weight percent of the mixture.
  • Using the composition as manufactured according to this invention, the compound that dissociates to choline is administered concomitantly with the drug. However the effect may be achieved when the compound is administered prior to the drug, but the period of time between the compound administration and the drug administration must be less than when acetylcholine concentration reduction begins to occur in the brain. Generally, the period of time between administrations is less than 36 hours, preferably less than 24 hours.

Claims (11)

1. The use of a drug and lecithin or a physiologically acceptable lecithin analog that dissociates to form choline to manufacture a medicament for concomitant use of the drug and lecithin or its analog in therapy wherein lecithin or its analog acts as an agent for increasing neuronal acetyl choline levels
1) to alleviate undesired side-effects of the drug caused by inadequate acetyl choline release occasioned by use of the drug, or
2) to potentiate the effectiveness of the drug in causing acetyl choline release, the lecithin or its analog being provided in an amount sufficient to cause a blood choline level of 10-50 nanomoles/ml.
2. The use of a drug and lecithin or a physiologically acceptable lecithin analog that dissociates to form choline to manufacture a medicament for sequential use of the drug and lecithin or its analog by administration of lecithin followed by the drug in therapy wherein lecithin or its analog acts as an agent for increasing neuronal acetyl choline levels
1) to alleviate undesired side-effects of the drug caused by inadequate acetyl choline release occasioned by use of the drug, or
2) to potentiate the effectiveness of the drug in causing acetyl choline release, the lecithin or its analog being provided in an amount sufficient to cause a blood choline level of 10-50 nanomoles/ml.
3. The use of a drug and lecithin or a physiologically acceptable lecithin analog according to claim 1 that dissociates to form choline to manufacture a medicament for concomitant use of the drug and lecithin in therapy wherein lecithin or its analog acts as an agent for increasing neuronal acetyl choline levels
1) to alleviate undesired side-effects of the drug caused by inadequate acetyl choline release occasioned by use of the drug, or
2) to potentiate the effectiveness of the drug in causing acetyl choline release, the lecithin or its analog being provided in an amount sufficient to cause a blood choline level of from 20 to 30 nanomoles/ml.
4. The use of a drug and lecithin or a physiologically acceptable lecithin analog according to claim 2, that dissociates to form choline to manufacture a medicament for sequential use of the drug and lecithin or its analog by administration of lecithin followed by the drug in therapy wherein lecithin or its analog acts as an agent for increasing neuronal acetyl choline levels
1) to alleviate undesired side-effects of the drug caused by inadequate acetyl choline release occasioned by use of the drug, or
2) to potentiate the effectiveness of the drug in causing acetyl choline release, the lecithin or its analog being provided in an amount sufficient to cause a blood choline level of from 20-30 nanomoles/ml.
5. The use according to claim 1, 2, 3 and 4, wherein the drug is chlorpromazine, haloperidol or a lithium salt.
6. The use according to claim 1, 2, 3, and 4 wherein the drug is amphetamine, methyl phenidate, phenytoin, phenobarbital or diazepam.
7. The use according to claim 1, 2, 3 or 4, wherein the drug is a dihydroergotamine or a gluco-cortico steroid.
8. The use according to claim 1, 2, 3 or 4, wherein the drug is isoxsuprine, prednisone, neostigmine or pyridostigmine.
9. The use according to any one of claims 1 to 8 wherein the medicament is in capsule or tablet form.
10. The use according to any one of claims 1 to 8 wherein the medicament is in liquid form.
11. The use as claimed in any one of claims 1 to 8 wherein the medicament is formulated for oral administration.
EP19780300587 1977-11-02 1978-11-02 Pharmaceutical composition for administering choline Expired EP0001924B2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US84796777A 1977-11-02 1977-11-02
US847967 1977-11-02

Publications (3)

Publication Number Publication Date
EP0001924A1 EP0001924A1 (en) 1979-05-16
EP0001924B1 EP0001924B1 (en) 1982-07-07
EP0001924B2 true EP0001924B2 (en) 1991-03-13

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ID=25301976

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EP19780300587 Expired EP0001924B2 (en) 1977-11-02 1978-11-02 Pharmaceutical composition for administering choline

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EP (1) EP0001924B2 (en)
CA (1) CA1114295A (en)
DE (1) DE2861944D1 (en)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2915433A1 (en) * 1979-04-17 1980-10-30 Christensen Plantorgan Werk USE OF PHYSIOLOGICALLY COMPATIBLE METHYLDONATORS
US4569929A (en) * 1980-02-29 1986-02-11 Massachusetts Institute Of Technology Cytidyl diphosphocholine-drug composition
NZ199722A (en) * 1981-02-25 1985-12-13 Genentech Inc Dna transfer vector for expression of exogenous polypeptide in yeast;transformed yeast strain
DE3479477D1 (en) * 1983-05-16 1989-09-28 Massachusetts Inst Technology A pharmaceutical composition for use in treating neurological disease or aging
US4626527A (en) * 1985-09-28 1986-12-02 Massachusetts Institute Of Technology Process for utilizing choline to sustain muscular performance
US5001117A (en) * 1989-03-07 1991-03-19 Pharmacaps, Inc. Use of lecithin to restore olfaction and taste
US6013273A (en) * 1997-01-27 2000-01-11 Novartis Nutrition Ag Treatment of endotoxic shock
WO2006010493A1 (en) * 2004-07-28 2006-02-02 Bayer Healthcare Ag Diagnostics and therapeutics for diseases associated with ethanolamine kinase 1 (ek11)
WO2006010489A2 (en) * 2004-07-28 2006-02-02 Bayer Healthcare Ag Diagnostics and therapeutics for diseases associated with choline kinase like protein (chkl)

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EP0001924A1 (en) 1979-05-16
DE2861944D1 (en) 1982-08-26
EP0001924B1 (en) 1982-07-07
CA1114295A (en) 1981-12-15

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